CaMKII mediates vascular smooth cell hypertrophy and hypertension

描述（由申请人提供）： 2000年，退伍军人事务部在治疗高血压上花费了超过1.5亿美元。然而，只有50%的退伍军人经常达到他们的血压目标，尽管多种药物。显然需要开发新的治疗策略来控制高血压。多功能钙/钙调素依赖性激酶II（CaMK II）在血管平滑肌（VSM）中大量表达，但其在VSM功能中的作用尚未得到深入研究。我们已经开发了新的，最先进的技术，研究CaMKII功能在血管平滑肌在体外和体外。我们的初步数据表明CaMKII是高血压的关键调节因子。具体而言，我们的初步研究表明：（1）CaMKII抑制减少体内和体外血管平滑肌肥大，和（2）主动脉和阻力血管中的血管收缩反应。(3)全身性CaMKII阻断可降低Ang-II高血压。 基于这些发现，我们假设：（1）在体内抑制VSM中的CaMK II降低高血压中的血管肥大和血管收缩反应，（2）CaMK II是VSM细胞肥大所必需的，（2）CaMK II通过HDAC 4去抑制诱导VSM细胞肥大。 我们将结合联合收割机的一些互补的，最先进的技术（分子生物学，蛋白质化学，细胞信号和生理学，动物生理学），解剖的VSM中的CaMK II信号的组件和CaMK II对高血压和中膜肥大的影响在体内。所有这些技术都在我们的实验室或我们合作者的实验室中。 公共卫生相关性： 对退伍军人医疗保健的潜在影响心血管疾病是美国最常见的死因。高血压是动脉粥样硬化、中风和心力衰竭发展的重要危险因素。2002年，总共有160万退伍军人接受了高血压治疗。2000年，退伍军人管理局仅在抗高血压药物上就花费了大约1.5亿美元。尽管有这些努力，50%的高血压治疗退伍军人没有达到他们的血压治疗目标。 仍然迫切需要开发新的概念来治疗高血压。本研究旨在探讨多功能钙/钙调素依赖性激酶II（CaMK II）在高血压、血管反应和血管平滑肌肥大中的作用。抑制CaMKII可能代表治疗高血压和预防血管重塑的新方法。

DESCRIPTION (provided by applicant): The Department of Veterans Affairs spent more than $150 million dollars on treatment of hypertension in 2000. However, only 50 % of all veterans achieve their blood pressure goals often despite polypharmacy. There is a clear need to develop new treatment strategies for controlling hypertension. The multifunctional calcium/ calmodulin-dependent kinase II (CaMKII) is abundantly expressed in vascular smooth muscle (VSM), however, its role in VSM function has not been intensively investigated. We have developed new, state of the art techniques to study CaMKII function in vascular smooth muscle in vitro and in vitro. Our preliminary data suggest CaMKII as a key regulator in hypertension. Specifically, our preliminary studies show that (1) CaMKII inhibition reduces vascular smooth muscle hypertrophy in vivo and in vitro, and (2) vasoconstrictor response in aorta and resistance blood vessels. (3) Systemic CaMKII blockade reduces Ang-II hypertension. Based on these findings, we hypothesize that (1) CaMKII inhibition in VSM in vivo decreases vascular hypertrophy and vasoconstrictor response in hypertension, (2) CaMKII is required for VSM cell hypertrophy, (2) that CaMKII induces VSM cell hypertrophy by HDAC4 derepression. We will combine a number of complementary, state of the art techniques (molecular biology, protein chemistry, cell signaling and physiology, animal physiology) to dissect the components of CaMKII signaling in VSM and the effect of CaMKII on hypertension and medial hypertrophy in vivo. All of these techniques are at hand in our laboratory or the laboratories of our collaborators. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans Health Care Cardiovascular diseases are the most frequent causes of death in the US. Hypertension is an important risk factor for the development of atherosclerosis, stroke and heart failure. Overall, 1.6 million veterans were treated for hypertension in 2002. In 2000, the VA spent an estimated 150 million dollars on antihypertensives alone. Despite these efforts, 50% of all veterans on treatment for hypertension do not reach their blood pressure treatment goals. There is still a pressing need for developing new concepts to treat hypertension. This proposal is aimed at investigating the role of the multifunctional calcium/calmodulin-dependent kinase II (CaMKII) in hypertension, vasomotor response and vascular smooth muscle hypertrophy. Inhibition of CaMKII could represent a novel approach to treating hypertension and preventing vascular remodeling.